Ischemic heart disease is responsible for the sudden death of over 500,000 U.S. citizens per year and is a leading public health problem in the United States. The pathophysiological sequelae following an acute myocardial infarction normally include depressed myocardial function leading to congestive heart failure and death. Thus, understanding the biochemical mechanisms responsible for ischemia-induced myocardial dysfunction, as well as reperfusion injury, represents a major U.S. health concern. One biochemical mechanism that likely contributes to myocardial dysfunction in ischemic myocardium is accelerated phospholipid catabolism. Since plasmalogens are the predominant phospholipid of myocardium, we have directed our efforts toward identifying accelerated plasmalogen catabolism during myocardial ischemia as a biochemical mechanism that mediates myocardial dysfunction during ischemia. We have previously demonstrated that plasmalogen-selective, calcium-independent phospholipase A2 (iPLA2) is activated in the membranes of ischemic myocardium and our preliminary studies now show that ischemic injury is reduced in hearts that are pretreated with the specific iPLA2 inhibitor, HELSS. We have also recently found that the nuclear membranes isolated from myocardium are enriched with plasmalogen molecular species and that catalytically-active iPLA2 is translocated to the nucleus during myocardial ischemia. These data suggest that accelerated nuclear membrane plasmalogen catabolism may participate in nuclear signaling responses that mediate alterations in myocardial gene expression. Additionally, we have recently discovered that myeloperoxidase, released from activated neutrophils, generates reactive chlorinating species that attack the vinyl ether bond of plasmalogens. These data suggest that cardiac myocyte and endothelial cell plasmalogens are targets for reactive chlorinating species produced by activated neutrophils during ischemia/reperfusion injury. Accordingly, the overall hypothesis of this proposal is that accelerated plasmalogen catabolism during myocardial ischemia and reperfusion is a key mechanism in cardiac injury and in nuclear signaling responses. We have three specific aims: Specific Aim 1 is to test the hypothesis that nuclear membrane plasmalogen catabolism is accelerated during myocardial ischemia and reperfusion. Specific Aim 2 is to test the hypothesis that accelerated plasmalogen catabolism mediates both cardiac injury and nuclear signaling responses during ischemia and reperfusion. Specific Aim 3 is to test the hypothesis that myocardial ischemia/reperfusion injury is mediated, in part, by plasmalogen degradation by reactive chlorinating species released from activated neutrophils.